Fxr signaling and microbial metabolism of bile salts in the zebrafish intestine
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ABSTRACT:
PROVIDER: PRJNA726184 | ENA |
REPOSITORIES: ENA
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Project description:The purpose of this study was to elucidate potential effects of fxr mutation on the functional specification of intestinal epithelial cells. To do this, we sorted GFP-positive cells from TgBAC(cldn15la:GFP) transgenics of either fxr+/+ or fxr-/- fish larvae and subjected them to 10X Genomics single-cell RNA-seq. Our results uncovered the requirement of fxr in gene expression and differentiation among multiple intestinal epithelial cell types.
2021-04-30 | GSE173570 | GEO
Project description:Obstruction of bile flow results in bacterial proliferation and mucosal injury in the small intestine that can lead to the translocation of bacteria across the epithelial barrier and systemic infection. These adverse effects of biliary obstruction can be inhibited by administration of bile acids. Here we show that the farnesoid X receptor (FXR), a nuclear receptor for bile acids, induces genes involved in enteroprotection and inhibits bacterial overgrowth and mucosal injury in ileum caused by bile duct ligation. Mice lacking FXR have increased ileal levels of bacteria and a compromised epithelial barrier. These findings reveal a central role for FXR in protecting the distal small intestine from bacterial invasion and suggest that FXR agonists may prevent epithelial deterioration and bacterial translocation in patients with impaired bile flow. In this report we have examined the role of FXR in the ileum. We demonstrate that it plays a crucial role in preventing bacterial overgrowth and maintaining the integrity of the intestinal epithelium
2012-07-19 | GSE39507 | GEO
Project description:The nuclear receptor FXR acts as an intracellular bile salt sensor that regulates synthesis and transport of bile salts within their enterohepatic circulation. In addition, FXR is involved in control of a variety of crucial metabolic pathways. Four FXR splice variants are known, i.e. FXRα1-4. Although these isoforms show differences in spatial and temporal expression patterns as well as in transcriptional activity, the physiological relevance hereof has remained elusive. We have evaluated specific roles of hepatic FXRα2 and FXRα4 by stably expressing these isoforms using liver-specific self-complementary adeno-associated viral vectors in total body FXR knock-out mice. The hepatic gene expression profile of the FXR knock-out mice was largely normalized by both isoforms. Yet, differential effects were also apparent; FXRα2 was more effective in reducing elevated HDL levels and transrepressed hepatic expression of Cyp8B1, the regulator of cholate synthesis. The latter coincided with a switch in hydrophobicity of the bile salt pool. Furthermore, FXRα2-transduction caused an increased neutral sterol excretion compared to FXRα4 without affecting intestinal cholesterol absorption. Our data show, for the first time, that hepatic FXRα2 and FXRα4 differentially modulate bile salt and lipoprotein metabolism in mice.
2014-11-11 | GSE51805 | GEO
Project description:Decreased bile secretion in rodents by either ligation of the common bile duct or induction of cirrhosis causes changes in the small intestine, including bacterial overgrowth and translocation across the mucosal barrier. Oral administration of bile acids inhibits these effects. The genes regulated by FXR in ileum suggested that it might contribute to the enteroprotective actions of bile acids. To test this hypothesis, mice were administered either GW4064 or vehicle for 2 days and then subjected to bile duct ligation (BDL) or sham operation. After 5 days, during which GW4064 or vehicle treatment was continued, the mice were killed and their intestines were analyzed for FXR target gene expression. Mice were treated with or without FXR ligand GW4064 for 2 days prior to bile duct ligation surgery and for 5 days after surgery. After 5 days the mice were sacrificed and the ileum collected and processed for gene expression analysis. Gene expression in the ilium from each sample group was assayed in duplicate using Affymetrix Mouse Genome 430A 2.0 Gene Chips.
2012-09-12 | E-GEOD-40821 | biostudies-arrayexpress
Project description:Specific bile acids are potent signaling molecules that modulate metabolic pathways affecting lipid, glucose and bile acid homeostasis, and the microbiota. Bile acids are synthesized from cholesterol in the liver, and the key enzymes involved in bile acid synthesis (Cyp7a1, Cyp8b1) are regulated transcriptionally by the nuclear receptor FXR. We have identified an FXR-regulated pathway upstream of a transcriptional repressor that controls multiple bile acid metabolism genes. We identify MafG as an FXR target gene and show that hepatic MAFG overexpression represses genes of the bile acid synthetic pathway and modifies the biliary bile acid composition. In contrast, loss-of-function studies using MafG(+/-) mice causes de-repression of the same genes with concordant changes in biliary bile acid levels. Finally, we identify functional MafG response elements in bile acid metabolism genes using ChIP-seq analysis. Our studies identify a molecular mechanism for the complex feedback regulation of bile acid synthesis controlled by FXR.
2016-02-04 | GSE77529 | GEO
Project description:Specific bile acids are potent signaling molecules that modulate metabolic pathways affecting lipid, glucose and bile acid homeostasis, and the microbiota. Bile acids are synthesized from cholesterol in the liver, and the key enzymes involved in bile acid synthesis (Cyp7a1, Cyp8b1) are regulated transcriptionally by the nuclear receptor FXR. We have identified an FXR-regulated pathway upstream of a transcriptional repressor that controls multiple bile acid metabolism genes. We identify MafG as an FXR target gene and show that hepatic MAFG overexpression represses genes of the bile acid synthetic pathway and modifies the biliary bile acid composition. In contrast, loss-of-function studies using MafG(+/-) mice causes de-repression of the same genes with concordant changes in biliary bile acid levels. Finally, we identify functional MafG response elements in bile acid metabolism genes using ChIP-seq analysis. Our studies identify a molecular mechanism for the complex feedback regulation of bile acid synthesis controlled by FXR.
2016-02-04 | GSE77529 | GEO
Project description:Decreased bile secretion in rodents by either ligation of the common bile duct or induction of cirrhosis causes changes in the small intestine, including bacterial overgrowth and translocation across the mucosal barrier. Oral administration of bile acids inhibits these effects. The genes regulated by FXR in ileum suggested that it might contribute to the enteroprotective actions of bile acids. To test this hypothesis, mice were administered either GW4064 or vehicle for 2 days and then subjected to bile duct ligation (BDL) or sham operation. After 5 days, during which GW4064 or vehicle treatment was continued, the mice were killed and their intestines were analyzed for FXR target gene expression.
2012-09-12 | GSE40821 | GEO
Project description:The inter-organ cross talk between liver and intestine has been focus of intense research. Key in this cross-talk are bile acids, which are secreted from the liver into the intestine and, via the enterohepatic circulation, reach back to the liver. Important new insights have been gained in the Farnesoid X receptor (Fxr)-mediated communication from intestine-to-liver in health and disease. However, liver-to-intestine communication and the role of bile acids and FXR in this cross talk remain elusive. Here, we analyse Fxr-mediated liver-to-gut communication, and its consequences in the colon. Mice in which Fxr was selectively ablated in intestine (Fxr-intKO), the liver (Fxr-livKO), or in the full body (Fxr-totKO) were engineered. The effects on colonic gene expression (RNA sequencing), on the microbiome (16S rRNA Gene Sequencing) and on mucus barrier were analyzed. Compared to Fxr-intKO and Fxr-totKO mice, more genes were differentially expressed in the colons of Fxr-livKO mice relative to control mice (731, 1824 and 3272 respectively), suggestive of a strong role of hepatic Fxr in liver-to-gut communication. The colons of Fxr-livKO showed increased expression of anti-microbial genes, such as Regenerating islet-derived 3 beta and gamma (Reg3β and Reg3γ), Toll-like receptors (Tlrs), inflammasome related genes and differential expression of genes belonging to the ‘Mucin-type O-glycan biosynthesis’ pathway. Compared to control mice, Fxr-livKO mice have decreased levels of the predicted mucin degrading bacterium Turicibacter and a concomitant increase in the thickness of the inner sterile mucus layer. In conclusion, ablation of Fxr in the liver has a major effect on colonic gene expression, the gut microbiome and on the permeability of the mucus layer. This stresses the importance of the Fxr-mediated liver-to-gut signaling.
2021-09-29 | GSE163157 | GEO
Project description:The farnesoid X receptor (FXR) is a nuclear receptor activated by bile acids and regulates bile acid metabolism, glucose and cholesterol homeostasis. From mouse studies we know that the novel FXR agonist obeticholic acid (OCA) regulates expression of many genes in the liver, but there is currently no data on the effects of OCA on human liver gene expression. This is especially relevant since the novel FXR agonist OCA is currently tested in clinical trials for the treatment of several diseases, such as nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD) and Type 2 Diabetes. In this study we investigate the effect of OCA treatment on gene expression profiles and localization of FXR to the genome in relevant liver samples. ChIP-Seq for FXR in Liver tissue from 2 male mice treated with OCA/INT-747 (10mg/kg/day) and 2 male mice treated with vehicle (1% methyl cellulose).
2016-01-27 | E-GEOD-73624 | biostudies-arrayexpress
Project description:The farnesoid X receptor (FXR) is a nuclear receptor activated by bile acids that regulates bile acid metabolism, glucose and cholesterol homeostasis. FXR is expressed as four isoforms (α1-4), and their relative abundance is tissue specific. Human livers express predominantly FXR isoforms α1 and α2. From mouse studies we know that the FXR agonist obeticholic acid (OCA) regulates expression of many genes in the liver. However, there is currently no data on the effects of OCA on FXR isoform selective gene regulation. This is particularly relevant since the relative FXR isoform amounts in the liver are regulated by general bioenergetic cues (Correia JC et al. 2015). In this study we investigate the effect of variations in FXR isoforms α1 or α2 expression on HepG2 cell lines response to treatment with OCA.
2020-07-27 | GSE133659 | GEO